ABSTRACT
Objective
To use superb microvascular imaging (SMI) to longitudinally evaluate blood flow in intravillous arterioles (IVA) in pregnancy, and to develop reference ranges for IVA pulsatility index (PI) and peak systolic velocity (PSV) from 12 to 38 weeks' gestation.
Methods
The data for this study were obtained from the National Institutes of Health‐funded Human Placenta Project. Eligible for inclusion were women aged 18–35 years, with a body mass index of < 30 kg/m2, without comorbidities, with a singleton pregnancy conceived spontaneously and a gestational age of ≤ 13 + 6 weeks. Exclusion criteria were maternal or neonatal complications, fetal or umbilical cord anomalies, abnormal placental implantation and delivery < 37 weeks. Each participant underwent eight ultrasound examinations during pregnancy. Using SMI technology, the total number of IVA identified was recorded in a sagittal placental section at the level of cord insertion. The PI and PSV were measured in a total of six IVA (two in the central portion of the placenta, two peripherally towards the uterine fundal portion and two peripherally towards the lower uterine segment). Umbilical artery (UA)‐PI was also obtained. Multilevel regression models were used to create reference ranges for IVA‐PI and IVA‐PSV at 12–38 weeks' gestation.
Results
A total of 90 women fulfilled the study criteria. IVA‐PI decreased throughout pregnancy from a mean ± SD of 1.04 ± 0.23 in the first trimester (at 12–13 weeks) to 0.75 ± 0.10 in the late third trimester (at 36–37 weeks). Mean IVA‐PSV increased from 5.97 ± 1.47 cm/s at 12–13 weeks to 12.65 ± 4.19 cm/s at 28–29 weeks, and then plateaued throughout the third trimester, to 13.09 ± 4.64 cm/s at 36–37 weeks. UA‐PI decreased progressively throughout pregnancy, from 1.49 ± 0.22 at 16–17 weeks to 0.89 ± 0.18 at 36–37 weeks. Reference ranges for IVA‐PI and IVA‐PSV from 12 to 38 weeks' gestation were developed.
Conclusion
Placental IVA blood flow can be visualized and quantified from early gestation in normal pregnancies using SMI. © 2025 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Keywords: Doppler, intravillous arteriole, placenta, superb microvascular imaging, umbilical artery
INTRODUCTION
At the junction of the umbilical cord and the placenta, the umbilical arteries branch to form chorionic arteries and traverse the fetal surface of the placenta in the chorionic plate; they then branch further within the placental tissue to form the intravillous arterioles (IVA), which carry deoxygenated and nutrient‐depleted blood from the fetus to the terminal villi 1 . Abnormal placental development in early gestation is associated with both maternal and fetal pathologic conditions that become apparent later in pregnancy, including fetal growth restriction, spontaneous preterm birth and pre‐eclampsia 2 , 3 , 4 , 5 , 6 . Until recently, our ability to further characterize this pathogenic mechanism of placental development has been limited by conventional ultrasound technology and the lack of non‐invasive tools that can be used during pregnancy 7 .
Superb microvascular imaging (SMI®) is a novel Doppler technique that enables the evaluation of placental microvasculature non‐invasively, by post‐processing of the color Doppler ultrasound signal 8 , 9 . It utilizes a multidimensional filter to preserve low‐velocity flow signals, as opposed to conventional Doppler, which uses a single‐dimension filter resulting in loss of low‐velocity flow signals 10 , 11 . SMI improves the visualization of microscopic vessels through an adaptive algorithm that can separate low‐velocity weak flow signals from overlying tissue motion artifacts, and display microvascular flow without the need for contrast agents. SMI evaluation of other organs, including thyroid, parathyroid, lymph nodes, breast, kidney and liver, has shown more detailed flow, with superior vessel continuity and visualization of smaller branches compared with conventional color and spectral Doppler evaluation 12 , 13 , 14 , 15 . To date, only one study has evaluated the use of SMI for the assessment of fetal placental vasculature 16 .
To assess whether quantitative measurement of flow in the IVA can predict adverse pregnancy outcomes, it is essential to establish normal IVA Doppler velocimetric values in pregnancy. The aim of this study was to use SMI to longitudinally evaluate color and spectral Doppler characteristics of IVA in normal singleton human pregnancies, and to develop reference ranges for use from 12 to 38 weeks' gestation.
METHODS
The data for this study were obtained as part of the National Institutes of Health (NIH)‐funded Human Placenta Project study (HD 086313‐01). Patients attending Macon and Joan Brock Virginia Health Sciences at Old Dominion University and University of Texas Medical Branch for prenatal care from January 2016 to March 2020 were invited to participate. Inclusion criteria were women aged 18–35 years, with a body mass index of < 30 kg/m2 and gestational age of ≤ 13 + 6 weeks at the time of recruitment. Exclusion criteria were maternal medical comorbidities, fetal or umbilical cord anomalies, abnormal placental implantation, multiple gestation, preterm delivery, any pregnancy or neonatal complication and conception via assisted reproductive technology. Abnormal placental implantation and umbilical cord abnormalities were defined as placenta previa, bilobed placenta and marginal or velamentous cord insertion at the time of recruitment in the first trimester. The current analysis is limited to uncomplicated singleton pregnancies delivered at ≥ 37 weeks' gestation.
Patients who fulfilled the inclusion criteria were considered to have a normal pregnancy and formed the reference population of the Human Placenta Project study. Written consent was obtained from all participants prior to participation. The study received approval from the Institutional Review Board prior to patient enrolment (No: 15‐09‐FB‐0179). The Maternal–Fetal Medicine ultrasound units at both institutions are accredited by the American Institute of Ultrasound in Medicine for obstetric ultrasound, including first‐ and second‐trimester ultrasound examinations. The As Low As Reasonably Achievable (ALARA) principle and ultrasound safety considerations were adhered to at all times 17 .
Ultrasound examinations began following enrolment at 12 + 0 to 13 + 6 weeks and were performed every 2 weeks until 16 weeks' gestation, then every 4 weeks until 37 weeks. This resulted in a total of eight ultrasound examinations per pregnancy, at the following gestational‐age windows: 12 + 0 to 13 + 6 weeks; 14 + 0 to 15 + 6 weeks; 16 + 0 to 17 + 6 weeks; 20 + 0 to 21 + 6 weeks; 24 + 0 to 25 + 6 weeks; 28 + 0 to 29 + 6 weeks; 32 + 0 to 33 + 6 weeks; and 36 + 0 to 37 + 6 weeks. All measurements were acquired transabdominally using Toshiba Aplio i800 ultrasound systems (Canon Medical, Tochigi, Japan) with an i8CX1 convex transducer. The five sonographers performing the ultrasound examinations were trained in the application of SMI and were required to pass a quality assurance review of five images prior to participating in the study. All ultrasound measurements were reviewed independently by two examiners (E.S., A.H.) to ensure quality. Prenatal care was otherwise at the discretion of the healthcare team and was unaffected by participation in the study, which forms part of our prospective, longitudinal Human Placenta Project study, and additional datapoints were collected at each ultrasound examination per the NIH study protocol.
Using SMI, IVA were identified on the fetal side of the placenta as they originate from the umbilical arteries (Figure 1) 12 . IVA were imaged in a sagittal section of the placenta, at the level of the cord insertion, and were assessed at three locations within the placenta: centrally, peripherally towards the fundus of the uterus and peripherally towards the lower uterine segment. The width of the cord insertion into the placenta was used to designate the location of the IVA, with central location defined as three cord widths around the cord insertion, and peripherally as outside this region, towards the fundus (fundal) and towards the lower uterine segment (lower segment).
Figure 1.
Superb microvascular image of a third‐trimester placenta, showing intravillous arterioles as they originate from the umbilical arteries.
The total number of IVA identified was recorded at the level of the cord insertion, in a sagittal placental section. The objective sonographic landmark of the cord insertion in the sagittal plane of the placenta was chosen to ensure consistency in the methodology for identifying the number of IVA. The pulsatility index (PI) and peak systolic velocity (PSV) were measured in a total of six IVA: two IVA in the central portion of the placenta, two peripheral IVA towards the uterine fundus and two peripheral IVA towards the lower uterine segment. All Doppler evaluations were performed with an insonation angle of ≤ 30° to ensure consistency and minimize angle‐related variability. Motion artifacts were minimized by ensuring that patients were in a comfortable supine position, and they were instructed to hold their breath briefly during Doppler acquisition. Mean IVA‐PI and IVA‐PSV values for each pregnancy were calculated by averaging the six associated measurements (central, fundal and lower segment). Umbilical artery (UA)‐PI was also obtained 18 , and the presence, absence or reversal of diastolic flow was noted.
Statistical analysis
Descriptive statistics are reported and analyzed using the chi‐square or Fisher's exact test, as appropriate, for categorical data; continuous data were analyzed using Student's t‐test. The correlation between IVA‐PI and UA‐PI across gestational timepoints was evaluated using Pearson's correlation coefficient, with results reported with 95% CIs. Longitudinal changes in IVA‐PSV and IVA‐PI were analyzed to assess differences between groups at each timepoint. IVA‐PSV and IVA‐PI for each gestational‐age timepoint were calculated by averaging the measurements in the central, fundal and lower segment locations. Distribution of response variables (Doppler) was assessed with quantile–quantile plots, skewness and kurtosis values. Doppler values were found to be right‐skewed across gestational age and were log‐transformed to achieve normality of the residuals. Response variables were modeled as a function of gestational age, and linear mixed‐effect regression with natural cubic splines was employed. Candidate models were compared with likelihood ratio tests. Model intercepts were allowed to vary between different individuals, and slopes were allowed to vary for the measurements of the same individual. Mean curve and SD were estimated separately using the approach suggested by Royston and Wright 19 . All models were checked for outliers, influential datapoints, normality of residuals and absence of autocorrelation in residuals. Outliers were either kept or removed from the model after double‐checking the veracity of the measurements. Model fit was assessed as described by Royston and Wright 20 by checking the normality of estimated Z‐scores across the fitted range and independency from gestational age. Statistical analysis was performed using SAS version 9.4 software (SAS Institute Inc., Cary, NC, USA), R for Statistical Computing software (version 4.2.0; R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism 9.3.1 (GraphPad, San Diego, CA, USA). P < 0.05 was considered statistically significant.
RESULTS
A total of 610 patients were enrolled in the Human Placenta Project from January 2016 to March 2020. Of these, 90 fulfilled the study criteria and formed the reference population for inclusion in this analysis. Maternal baseline demographic characteristics and placental location are given in Table 1. The mean number of IVA visualized in a sagittal plane of the placenta increased from 7.62 ± 1.87 at 12–13 weeks' gestation to 18.87 ± 4.47 in the late third trimester (36–37 weeks) (Table 2). Mean IVA‐PI decreased progressively throughout pregnancy, from 1.04 ± 0.23 in the first trimester (12–13 weeks) to 0.75 ± 0.10 in the late third trimester (36–37 weeks) (Table 2, Figure 2a). Mean IVA‐PSV increased progressively until 28 weeks from a mean of 5.97 ± 1.47 cm/s at 12–13 weeks to a mean of 12.65 ± 4.19 cm/s at 28–29 weeks (Table 2, Figure 2b). Thereafter, IVA‐PSV plateaued throughout the third trimester, reaching a mean of 13.09 ± 4.64 cm/s at 36–37 weeks. No difference in IVA‐PI or IVA‐PSV was observed based on IVA location within the placenta (central, fundal or lower segment) at any gestational‐age timepoint assessed (Figures S1 and S2).
Table 1.
Maternal demographic characteristics and placental location in 90 patients with normal singleton pregnancy included in study
| Characteristic | Value |
|---|---|
| Age (years) | 25.52 ± 4.08 |
| Height (cm) | 163.29 ± 7.95 |
| Weight (kg) | 63.73 ± 10.36 |
| Body mass index (kg/m2) | 23.62 ± 3.20 |
| Race | |
| White | 39 (43.3) |
| Black/African American | 50 (55.6) |
| Asian | 0 (0) |
| American Indian or Native American | 0 (0) |
| Native Hawaiian or other Pacific Islander | 0 (0) |
| Other | 1 (1.1) |
| Ethnicity | |
| Hispanic/Latino/Latina | 7 (7.8) |
| Not Hispanic/Latino/Latina | 83 (92.2) |
| Placental location | |
| Anterior | 45 (50.0) |
| Posterior | 38 (42.2) |
| Right lateral | 1 (1.1) |
| Left lateral | 1 (1.1) |
| Not reported | 5 (5.6) |
Data are given as mean ± SD or n (%).
Table 2.
Longitudinal assessment of number of intravillous arterioles (IVA) visualized in sagittal plane of the placenta, IVA pulsatility index (PI) and IVA peak systolic velocity (PSV), according to gestational age
| Gestational age | Number of IVA | IVA‐PI | IVA‐PSV (cm/s) |
|---|---|---|---|
| 12–13 weeks | 7.62 ± 1.87 | 1.04 ± 0.23 | 5.97 ± 1.47 |
| 14–15 weeks | 9.08 ± 2.36 | 1.03 ± 0.18 | 6.33 ± 1.16 |
| 16–17 weeks | 11.44 ± 2.32 | 0.98 ± 0.15 | 7.14 ± 1.27 |
| 20–21 weeks | 13.75 ± 2.78 | 0.97 ± 0.13 | 9.04 ± 2.10 |
| 24–25 weeks | 14.94 ± 3.11 | 0.94 ± 0.12 | 10.90 ± 3.04 |
| 28–29 weeks | 17.28 ± 3.26 | 0.89 ± 0.10 | 12.65 ± 4.19 |
| 32–33 weeks | 18.11 ± 4.07 | 0.81 ± 0.10 | 12.49 ± 4.02 |
| 36–37 weeks | 18.87 ± 4.47 | 0.75 ± 0.10 | 13.09 ± 4.64 |
Data are given as mean ± SD.
Figure 2.
Scatterplots showing longitudinal changes in intravillous arteriole pulsatility index (PI) (a), intravillous arteriole peak systolic velocity (PSV) (b) and umbilical artery PI (c), according to gestational age, in normal singleton pregnancy. Median (
) and 5th and 95th percentiles (
) are shown.
UA‐PI was assessed from 16 weeks and was observed to decrease progressively throughout pregnancy, from a mean of 1.49 ± 0.22 at 16–17 weeks to 0.89 ± 0.18 at 36–37 weeks (Table S1, Figure 2c). Multilevel regression models were used to create reference ranges for UA‐PI in our normal pregnancy population, from 16 to 38 weeks, and are presented in Table S2. There was a moderate positive correlation between central IVA and UA‐PI values, with a correlation coefficient of 0.49 (95% CI, 0.42–0.57).
Reference ranges for IVA‐PI and IVA‐PSV from 12 to 38 weeks were derived using multilevel regression models in our population of normal pregnancies, and are presented in Tables 3 and 4, respectively. Cut‐off values defining abnormal IVA‐PI and IVA‐PSV should await studies that include complicated pregnancies with adverse outcomes; however, statistical cut‐offs can be defined by a mean IVA‐PSV and mean IVA‐PI > 95th percentile.
Table 3.
Intravillous arteriole pulsatility index reference ranges from 12 to 38 weeks' gestation, in normal singleton pregnancy
| Intravillous arteriole pulsatility index | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Gestational age | 3rd per | 5th per | 10th per | 25th per | Median | 75th per | 90th per | 95th per | 97th per |
| 12 weeks | 0.78 | 0.80 | 0.85 | 0.93 | 1.03 | 1.14 | 1.25 | 1.31 | 1.36 |
| 13 weeks | 0.77 | 0.80 | 0.84 | 0.92 | 1.02 | 1.13 | 1.24 | 1.30 | 1.35 |
| 14 weeks | 0.77 | 0.80 | 0.84 | 0.92 | 1.02 | 1.12 | 1.23 | 1.30 | 1.34 |
| 15 weeks | 0.77 | 0.79 | 0.84 | 0.92 | 1.01 | 1.12 | 1.22 | 1.29 | 1.33 |
| 16 weeks | 0.76 | 0.79 | 0.83 | 0.91 | 1.00 | 1.11 | 1.21 | 1.28 | 1.32 |
| 17 weeks | 0.76 | 0.79 | 0.83 | 0.91 | 1.00 | 1.10 | 1.20 | 1.26 | 1.31 |
| 18 weeks | 0.76 | 0.78 | 0.82 | 0.90 | 0.99 | 1.09 | 1.19 | 1.25 | 1.30 |
| 19 weeks | 0.75 | 0.78 | 0.82 | 0.89 | 0.98 | 1.08 | 1.18 | 1.24 | 1.28 |
| 20 weeks | 0.75 | 0.77 | 0.81 | 0.89 | 0.97 | 1.07 | 1.17 | 1.23 | 1.27 |
| 21 weeks | 0.74 | 0.77 | 0.81 | 0.88 | 0.96 | 1.06 | 1.15 | 1.21 | 1.25 |
| 22 weeks | 0.74 | 0.76 | 0.80 | 0.87 | 0.95 | 1.05 | 1.14 | 1.20 | 1.24 |
| 23 weeks | 0.73 | 0.75 | 0.79 | 0.86 | 0.94 | 1.03 | 1.12 | 1.18 | 1.22 |
| 24 weeks | 0.72 | 0.74 | 0.78 | 0.85 | 0.93 | 1.02 | 1.11 | 1.16 | 1.20 |
| 25 weeks | 0.71 | 0.73 | 0.77 | 0.84 | 0.92 | 1.00 | 1.09 | 1.14 | 1.18 |
| 26 weeks | 0.70 | 0.72 | 0.76 | 0.82 | 0.90 | 0.99 | 1.07 | 1.12 | 1.16 |
| 27 weeks | 0.69 | 0.71 | 0.75 | 0.81 | 0.89 | 0.97 | 1.05 | 1.10 | 1.14 |
| 28 weeks | 0.68 | 0.70 | 0.74 | 0.80 | 0.87 | 0.95 | 1.03 | 1.08 | 1.12 |
| 29 weeks | 0.67 | 0.69 | 0.73 | 0.79 | 0.86 | 0.94 | 1.01 | 1.06 | 1.09 |
| 30 weeks | 0.66 | 0.68 | 0.71 | 0.77 | 0.84 | 0.92 | 0.99 | 1.04 | 1.07 |
| 31 weeks | 0.65 | 0.67 | 0.70 | 0.76 | 0.82 | 0.90 | 0.97 | 1.02 | 1.05 |
| 32 weeks | 0.64 | 0.66 | 0.69 | 0.74 | 0.81 | 0.88 | 0.95 | 1.00 | 1.03 |
| 33 weeks | 0.63 | 0.64 | 0.68 | 0.73 | 0.79 | 0.86 | 0.93 | 0.97 | 1.00 |
| 34 weeks | 0.61 | 0.63 | 0.66 | 0.71 | 0.78 | 0.84 | 0.91 | 0.95 | 0.98 |
| 35 weeks | 0.60 | 0.62 | 0.65 | 0.70 | 0.76 | 0.83 | 0.89 | 0.93 | 0.96 |
| 36 weeks | 0.59 | 0.61 | 0.64 | 0.69 | 0.74 | 0.81 | 0.87 | 0.91 | 0.94 |
| 37 weeks | 0.58 | 0.60 | 0.62 | 0.67 | 0.73 | 0.79 | 0.85 | 0.89 | 0.91 |
| 38 weeks | 0.57 | 0.59 | 0.61 | 0.66 | 0.71 | 0.77 | 0.83 | 0.87 | 0.89 |
Per, percentile.
Table 4.
Intravillous arteriole peak systolic velocity reference ranges from 12 to 38 weeks' gestation, in normal singleton pregnancy
| Peak systolic velocity (cm/s) | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Gestational age | 3rd per | 5th per | 10th per | 25th per | Median | 75th per | 90th per | 95th per | 97th per |
| 12 weeks | 3.56 | 3.73 | 4.00 | 4.51 | 5.14 | 5.87 | 6.61 | 7.10 | 7.43 |
| 13 weeks | 3.78 | 3.96 | 4.26 | 4.80 | 5.48 | 6.25 | 7.05 | 7.57 | 7.93 |
| 14 weeks | 4.02 | 4.21 | 4.53 | 5.11 | 5.83 | 6.67 | 7.52 | 8.08 | 8.46 |
| 15 weeks | 4.26 | 4.47 | 4.81 | 5.42 | 6.21 | 7.10 | 8.02 | 8.62 | 9.04 |
| 16 weeks | 4.51 | 4.73 | 5.09 | 5.75 | 6.60 | 7.56 | 8.55 | 9.20 | 9.65 |
| 17 weeks | 4.75 | 4.99 | 5.37 | 6.09 | 7.00 | 8.04 | 9.12 | 9.83 | 10.32 |
| 18 weeks | 4.98 | 5.23 | 5.65 | 6.42 | 7.41 | 8.55 | 9.72 | 10.50 | 11.04 |
| 19 weeks | 5.19 | 5.46 | 5.91 | 6.75 | 7.83 | 9.07 | 10.36 | 11.22 | 11.81 |
| 20 weeks | 5.38 | 5.68 | 6.16 | 7.08 | 8.25 | 9.61 | 11.03 | 11.98 | 12.64 |
| 21 weeks | 5.55 | 5.87 | 6.40 | 7.38 | 8.66 | 10.15 | 11.72 | 12.77 | 13.50 |
| 22 weeks | 5.70 | 6.04 | 6.61 | 7.67 | 9.06 | 10.69 | 12.41 | 13.57 | 14.38 |
| 23 weeks | 5.83 | 6.20 | 6.80 | 7.94 | 9.44 | 11.21 | 13.10 | 14.37 | 15.26 |
| 24 weeks | 5.95 | 6.33 | 6.97 | 8.19 | 9.80 | 11.72 | 13.76 | 15.16 | 16.14 |
| 25 weeks | 6.05 | 6.45 | 7.13 | 8.42 | 10.13 | 12.20 | 14.40 | 15.91 | 16.98 |
| 26 weeks | 6.14 | 6.56 | 7.27 | 8.64 | 10.45 | 12.64 | 15.01 | 16.64 | 17.78 |
| 27 weeks | 6.23 | 6.67 | 7.41 | 8.84 | 10.74 | 13.06 | 15.57 | 17.30 | 18.52 |
| 28 weeks | 6.32 | 6.78 | 7.54 | 9.03 | 11.01 | 13.44 | 16.07 | 17.89 | 19.18 |
| 29 weeks | 6.42 | 6.89 | 7.68 | 9.21 | 11.26 | 13.78 | 16.51 | 18.41 | 19.75 |
| 30 weeks | 6.53 | 7.01 | 7.82 | 9.38 | 11.49 | 14.07 | 16.88 | 18.83 | 20.21 |
| 31 weeks | 6.66 | 7.14 | 7.96 | 9.56 | 11.70 | 14.32 | 17.18 | 19.16 | 20.57 |
| 32 weeks | 6.79 | 7.28 | 8.12 | 9.72 | 11.89 | 14.54 | 17.42 | 19.42 | 20.83 |
| 33 weeks | 6.93 | 7.43 | 8.27 | 9.89 | 12.07 | 14.72 | 17.61 | 19.60 | 21.02 |
| 34 weeks | 7.08 | 7.58 | 8.43 | 10.05 | 12.23 | 14.88 | 17.75 | 19.73 | 21.13 |
| 35 weeks | 7.24 | 7.75 | 8.59 | 10.22 | 12.38 | 15.01 | 17.85 | 19.80 | 21.18 |
| 36 weeks | 7.41 | 7.92 | 8.76 | 10.38 | 12.53 | 15.13 | 17.93 | 19.84 | 21.19 |
| 37 weeks | 7.58 | 8.09 | 8.93 | 10.54 | 12.67 | 15.23 | 17.98 | 19.85 | 21.17 |
| 38 weeks | 7.76 | 8.27 | 9.11 | 10.70 | 12.81 | 15.33 | 18.02 | 19.85 | 21.14 |
Per, percentile.
DISCUSSION
In this study, we have demonstrated the ability of SMI to assess fetal placental microvasculature, beginning in early pregnancy. We have also demonstrated that fetal placental vessels continue to undergo adaptation throughout normal pregnancy, with a progressive decrease in mean IVA‐PI throughout pregnancy, and a progressive increase in IVA‐PSV until the early third trimester, followed by a subsequent plateau.
Optimal placental function during pregnancy requires the establishment of adequate vascularization in early pregnancy. This begins approximately 21 days after conception, with villi undergoing initial vasculogenesis and blood vessel formation 21 . Branching angiogenesis is then believed to occur within the placenta, allowing the formation of new branches from pre‐existing vessels to meet the increasing metabolic demands of the growing fetus 22 . This is consistent with our finding of an increasing number of IVA visualized using SMI as gestational age increased.
In our normal pregnancy cohort, IVA‐PI decreased progressively during pregnancy. Kurjak et al. 23 assessed IVA blood flow throughout normal pregnancy using conventional Doppler and reported that IVA‐PI decreased progressively until the mid‐second trimester, and then remained stable. Our observations of a progressive decrease in IVA‐PI throughout pregnancy may be due to our strict definition of normal pregnancy, the ability to better visualize intravillous vessels using novel SMI technology and the longitudinal aspect of our study. Kurjak et al. also noted that IVA‐PSV increased progressively until the mid‐second trimester and then plateaued, before decreasing at term 23 . Our study showed a continual increase in IVA‐PSV throughout pregnancy, with a plateau in the third trimester.
This study demonstrates that IVA‐PI and IVA‐PSV measurements are unaffected by placental sampling location. Therefore, we suggest obtaining IVA Doppler indices within the central portion of the placenta, as it is the thickest placental portion and thus technically easier to visualize. At present, it remains unknown if Doppler abnormalities of IVA observed in complicated pregnancies are affected by sampling location within the placenta. Our proposed cut‐off of > 95th percentile for mean IVA‐PSV and IVA‐PI at a given gestational age will also need to be confirmed by future studies that assess complicated pregnancies with adverse outcomes.
We noted a progressive decrease in UA‐PI throughout normal pregnancy. This is consistent with previous findings assessing UA blood flow in normal pregnancy 24 . The presence of UA end‐diastolic flow is first evident at the end of the first trimester, with a subsequent increase in end‐diastolic flow throughout gestation, which is believed to result from a decrease in fetoplacental vascular impedance and a resultant rise in fetal blood pressure 24 , 25 , 26 .
Our ability to assess the human placenta non‐invasively throughout pregnancy has previously been limited by conventional ultrasound technology. Evaluation of the pathophysiological processes that occur during abnormal placental development in early gestation has been greatly improved with the development of novel ultrasound technology, such as SMI. Knowledge of normal values of fetal placental vasculature throughout pregnancy is a key step in identifying those pregnancies that are affected by abnormal development of fetal placental vasculature. We have previously demonstrated the ability to image and quantify spiral artery blood flow in the same cohort of normal pregnancies, starting from early gestation, and have developed reference ranges for spiral artery PSV and PI throughout pregnancy 27 .
Our study has several strengths. It was a large, prospective, longitudinal study with data obtained from eight ultrasound examinations at predefined timepoints throughout pregnancy. To our knowledge, this is the first study to assess IVA using novel ultrasound technology, and it is the first study to longitudinally assess the vascular adaptation of IVA in normal pregnancy using SMI. Our strict selection criteria for inclusion in our cohort ensured that the nomogram is reflective of fetal vascular adaptation in normal pregnancies. Limitations of our study include the required expertise and training of sonographers and physicians prior to the use of SMI, which may limit its wide applicability at present. An additional limitation of this study is the potentially subjective nature of identifying placental vasculature, since it depends on the expertise of the operator and placental location within the uterus.
In conclusion, we have demonstrated the ability to both visualize and quantify IVA blood flow in normal pregnancies, beginning in the first trimester, and developed reference ranges for IVA‐PI and IVA‐PSV from 12 to 38 weeks' gestation.
Supporting information
Figures S1 and S2 Longitudinal changes in mean intravillous arteriole pulsatility index (IVA‐PI) (Figure S1) and mean intravillous arteriole peak systolic velocity (IVA‐PSV) (Figure S2) by location within the placenta, in normal singleton pregnancy.
Table S1 Longitudinal assessment of umbilical artery pulsatility index in normal singleton pregnancy
Table S2 Umbilical artery pulsatility index reference ranges from 16 to 38 weeks' gestation, in normal singleton pregnancy
ACKNOWLEDGMENT
The Human Placenta Project study (HD 086313‐01) was funded by the National Institutes of Health (NIH).
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Figures S1 and S2 Longitudinal changes in mean intravillous arteriole pulsatility index (IVA‐PI) (Figure S1) and mean intravillous arteriole peak systolic velocity (IVA‐PSV) (Figure S2) by location within the placenta, in normal singleton pregnancy.
Table S1 Longitudinal assessment of umbilical artery pulsatility index in normal singleton pregnancy
Table S2 Umbilical artery pulsatility index reference ranges from 16 to 38 weeks' gestation, in normal singleton pregnancy
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.